Structural Superimposition

Abstact

Bacteria deploy virulence factors to subvert host immunity; yet the molecular details of these interactions often remain limited. Here, we reveal the structure and host interactome of the Streptococcus pyogenes nuclease A (SpnA). We characterize the structure and dynamics of SpnA using hydrogen-deuterium exchange mass spectrometry and single-particle electron cryo microscopy, yielding the first structural insights to SpnA. This allowed us to identify an additional oligonucleotide-binding domain, whose flexible structure may play an important function in nucleolytic activity. Affinity-pulldown mass spectrometry identified the complement system membrane attack complex (MAC) C5b67 components as key interactors. Cross-linking mass spectrometry combined with integrative modeling identified the binding interfaces between SpnA and C5b67. These interfaces are conserved among genetically diverse S. pyogenes strains. Interaction between SpnA and C5b67 is suggested to prevent the assembly of a functional MAC. Our findings uncover a novel function of SpnA in complement inhibition, and identifies new potential targets to prevent and treat S. pyogenes infections.